Abstract
The mechanisms responsible for the development of resistance to alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, are still unclear, and few cell lines are currently available for investigating ALK-rearranged lung cancer. To identify the mechanisms underlying acquired resistance to alectinib, two patient-derived cell lines were established from an alectinib-naïve ALK-rearranged lung cancer and then after development of alectinib resistance. The properties acquired during treatments were detected by comparisons of the two cell lines, and then functional analyses were performed. Coactivation of c-Src and MET was identified after the development of alectinib resistance. Combinatorial therapy against Src and MET significantly restored alectinib sensitivity in vitro (17.2-fold). Increased apoptosis, reduction of tumor volume, and inhibition of MAPK and PI3K/AKT signaling molecules for proliferation and survival were observed when the three kinases (Src, MET, and ALK) were inhibited. A patient-derived xenograft from the alectinib-resistant cells indicated that combination therapy with a saracatinib and crizotinib significantly decreased tumor size in vivo. To confirm the generality, a conventional alectinib-resistant cell line model (H2228-AR1S) was established from NCI-H2228 cells (EML4-ALK variant 3a/b). In H2228-AR1S, combination inhibition of Src and MET also restored alectinib sensitivity. These data reveal that dual salvage signaling from MET and Src is a potential therapeutic target in alectinib-resistant patients. IMPLICATIONS: This study demonstrates the feasibility to elucidate personalized drug-resistance mechanisms from individual patient samples.
Highlights
The discovery of driver oncogenes and development of targeted therapy have contributed to improved prognoses in patients with non–small cell lung cancer (NSCLC; refs. 1, 2)
Secondary mutations have been implicated as frequent causes of anaplastic lymphoma kinase (ALK) inhibitor resistance than salvage signaling, and one possible explanation for this is that crizotinib exhibits relatively low affinity to ALK and targets multiple tyrosine kinases, such as c-MET and ROS1
Establishment of a clinical paired resistant model The clinical paired resistant model (CPRM) for alectinib consisted of 2 cell lines, KTOR1 and KTOR1-RE (EML4-ALK variant 1 E13; A20), which were established from a patient with ALKrearranged NSCLC who regularly visited Kyoto University Hospital
Summary
The discovery of driver oncogenes and development of targeted therapy have contributed to improved prognoses in patients with non–small cell lung cancer (NSCLC; refs. 1, 2). The discovery of driver oncogenes and development of targeted therapy have contributed to improved prognoses in patients with non–small cell lung cancer 5), tumors relapsed due to the acquisition of resistance Secondary mutations, such as L1196M, C1156Y, and G1202R, occur in the kinase domain of. ALK and decrease the affinity of crizotinib to ALK and maintain EML4-ALK activity [6,7,8] Salvage signaling pathways, such as EGFR and KIT, maintain downstream proliferation and survival signaling, such as PI3K/Akt or MAPK, independent of the ALKfusion protein, which promotes growth and survival if oncogenic ALK signaling is inhibited [8, 9]. Secondary mutations have been implicated as frequent causes of ALK inhibitor resistance than salvage signaling, and one possible explanation for this is that crizotinib exhibits relatively low affinity to ALK and targets multiple tyrosine kinases, such as c-MET and ROS1
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